ATP (adenosine triphosphate) is known to serve as a source of energy in cells and a substrate of phosphorylation, as well as an extracellular messenger. It is known that ATP is released from a cell by various stimulation such as cellular injury, inflammation, nociceptive stimulus, reduced blood oxygen level, and also known to be released together with another messenger from a primary sensory nerve terminal. ATP thus released mediates various extracellular signal transductions through an ATP receptor (Non-Patent Document 6, Non-Patent Document 7).
ATP receptor is categorized into ionotropic P2X family and G protein-coupled P2Y family. For P2X family, seven subtypes have been reported, and a member of this family forms a homo-trimeric structure or a hetero-trimeric structure together with another member of this subtype and functions as a non-specific cation channel (Non-Patent Document 8).
ATP is known to cause pain, and studies with P2X3 knockout and knockdown methodologies have shown that P2X3 receptor mediates transmission of chronic pain. P2X3 receptors are expressed in a specific manner on peripheral sensory nerve to form a homo-complex or hetero-complex with P2X2 (P2X2/3) (Non-Patent Document 1).
Later, the compound A-317491 was reported as a specific antagonist to P2X3 and P2X2/3 receptors. A-317491 is tri-substituted-N-[(1S)-1,2,3,4-tetrahydro-1-naphthalenyl]benzamide derivative represented by the formula:
(Patent Document 1). It was reported to exhibit an antagonist activity to P2X3 and P2X2/3 receptors and analgesic action in neuropathic pain model and inflammatory pain model (Non-Patent Document 9). This indicates that pain sensation is transmitted via P2X3 or P2X2/3 receptor and that a P2X3 or P2X2/3 receptor antagonist is useful as an analgesic. Also, compounds that exhibit P2X3 or P2X2/3 receptor antagonizing effect are described in Patent Documents 2-7.
Additionally, it was recently reported that vesical reflex was strongly reduced in P2X3 knockout mouse (Non-Patent Document 2), suggesting that a P2X3 antagonist is useful in the treatment of diseases caused by overactive bladder.
Non-Patent Documents 3 and 4 disclose that the compounds having similar structures to the compounds of the invention show an analgetic activity. However, the structures of these compounds differ from the compounds of the invention.    [Patent Document 1] WO02/094767    [Patent Document 2] WO2005/095359    [Patent Document 3] US20070037974    [Patent Document 4] US20070049758    [Patent Document 5] US20070049610    [Patent Document 6] US20070049609    [Patent Document 7] US20070049534    [Non-Patent Document 1] Neuroscientist 11 (2005) pp. 345-356    [Non-Patent Document 2] J. Physiol. 567.2 (2005) pp. 621-639    [Non-Patent Document 3] Pharmaceutical Chemistry Journal Vol. 39, No. 9, (2005), pp 484-487    [Non-Patent Document 4] Pharmaceutical Chemistry Journal Vol. 31, No. 5, (1997), pp 251-254    [Non-Patent Document 5] Expert Opin. Ther. Patens (2006) 16 (8) 113-1127.    [Non-Patent Document 6] J. Physiology (2003), 554 (2), 301-308    [Non-Patent Document 7] J. Physiology (2003), 553 (3), 683-694    [Non-Patent Document 8] Pflungers Arch Eur J physiol (2006), 452, 513-537    [Non-Patent Document 9] PNAS (2002), 99 (26), 17179-17184